The invention relates to compositions comprising a retinoic acid receptor antagonist capable of promoting angiogenesis. The invention also relates to methods of treating medical conditions associated with suboptimal angiogenesis.
A number of studies have demonstrated that retinoids (vitamin A derivatives) are essential for normal growth, vision, tissue homeostasis, reproduction and overall survival (for reviews and references, see Sporn et al., The Retinoids, Vols. 1 and 2, Sporn et al., eds., Academic Press, Orlando, Fla. (1984)).
Except for those involved in visual perception (Wald, G. et al., Science 162:230-239 (1968)), the molecular mechanisms underlying the highly diverse effects of retinoids have until recently remained obscure. The discovery of nuclear receptors for retinoic acid (RA) (Petkovich et al., Nature 330:444-450 (1987); Giguxc3xa8re et al., Nature 330:624-629 (1987)) has greatly advanced the understanding of how the retinoids may exert their pleiotropic effects (Leid, M., et al., TIBS 17:427-433 (1992); Linney, E., Current Topics in Dev. Biol. 27:309-350 (1992)). It is thought that the effects of the RA signal are mediated through two families of receptorsxe2x80x94the RAR family and RXR familyxe2x80x94which belong to the superfamily of ligand-inducible transcriptional regulatory factors that include steroid/thyroid hormone and vitamin D3 receptors (for reviews, see Leid, M., et al., TIBS 17:427-433 (1992); Chambon, P., Semin. Cell Biol. 5:115-125 (1994); Chambon, P., FASEB J. 10:940-954 (1996); Giguere, V., Endocrinol. Rev. 15:61-79 (1994); Mangelsdorf, D. J., and Evans, R. M., Cell 83:841-850 (1995); Gronemeyer, H., and Laudet, V., Protein Profile 2:1173-1236 (1995)).
Receptors belonging to the retinoic acid receptor family (RARxcex1, xcex2 and xcex3 and their isoforms) are activated by both all-trans- and 9-cis-RA (Leid, M., et al., TIBS 17:427-433 (1992); Chambon, P., Semin. Cell Biol. 5:115-125 (1994); Dollxc3xa9, P., et al., Mech. Dev. 45:91-104 (1994)). Unlike the RARs, members of the retinoid X receptor family (RXRxcex1, xcex2 and xcex3) are activated exclusively by 9-cis- RA (Chambon, P., Semin. Cell Biol. 5:115-125 (1994); Dollxc3xa9, P., et al., Mech. Dev. 45:91-104 (1994); Linney, E., Current Topics in Dev. Biol. 27:309-350 (1992); Leid, M., et al., TIBS 17:427-433 (1992); Kastner et al., In: Vitamin A in Health and Disease, R. Blomhoff, ed., Marcel Dekker, New York (1993)).
It has been shown that activation of RA-responsive promoters likely occurs through RAR/RXR heterodimers rather than through homodimers (Yu, V. C., et al., Cell 67:1251-1266 (1991); Leid, M., et al., Cell 68:377-395 (1992b); Durand et al., Cell 71:73-85 (1992); Nagpal, S., et al., Cell 70:1007-1019 (1992); Zhang, X. K., et al., Nature 355, 441-446 (1992); Kliewer et al., Nature 355:446-449 (1992); Bugge et al., EMBO J. 11:1409-1418 (1992); Marks et al., EMBO J. 11:1419-1435 (1992); Yu, V. C. et al., Cur. Op. Biotech. 3:597-602 (1992); Leid, M., et al., TIBS 17:427-433 (1992); Laudet and Stehelin, Curr. Biol. 2:293-295 (1992); Green, S., Nature 361:590-591 (1993)). The RXR portion of these heterodimers has been proposed to be silent in retinoid-induced signaling (Kurokawa, R., et al., Nature 371:528-531 (1994); Forman, B. M., et al., Cell 81:541-550 (1995); Mangelsdorf, D. J., and Evans, R. M., Cell 83:835-850 (1995); Vivat, V. et al., EMBO J. 16:5697-5709 (1997)) but conflicting results have been reported as far as the ligand-binding ability of RXR in heterodimers is concerned (Kurokawa, R., et al., Nature 371:528-531 (1994); Chen, J.-Y. et al., Nature 382:819-822 (1996); Kersten, S. et al., Biochem. 35:3816-3824 (1996); Chen, Z. et al., J. Mol. Biol. 275:55-65 (1998); Li, C. et al., Proc. Natl. Acad. Sci. USA 94:2278-2283 (1997). The results of these and of genetic studies strongly suggest that RAR/RXR heterodimers are indeed functional units that transduce the RA signal in vivo (Chambon, P., Semin. Cell Biol. 5:115-125 (1994); Kastner, P. et al., Cell 83:859-869 (1995); Mascrez, B. et al., Development 125:4691-4707 (1998)). Thus, the basis for the highly pleiotropic effect of retinoids may reside, at least in part, in the control of different subsets of retinoid-responsive promoters by cell-specifically expressed heterodimeric combinations of RAR/RXR subtypes (and isoforms), whose activity may be in turn regulated by cell-specific levels of all-trans- and 9-cis-RA (Leid, M., et al., TIBS 17:427-433 (1992)).
Angiogenesis is a complex multistep process involving the formation of new blood vessels from preexisting vessels. The mammalian vasculature consists of large arteries that branch into smaller vessels turning into precapillary arterioles that terminate into a capillary network. The vessel wall is composed of endothelial, smooth muscle and fibroblast cells. Capillaries, on the other hand, are comprised almost entirely of endothelial cells. The endothelium plays a prominent role in the vascular function, being constantly exposed to cytokines, vasoactive factors, procoagulants and mechanical signals (Ross, 1993). Angiogenesis is dependent on endothelial cell migration, proliferation, proteolytic activity and morphogenesis (Hanahan, 1996).
A number of growth factors, such as VEGF and bFGF, are known to positively affect angiogenesis. Such therapeutic manipulation of vessel growth is an attractive approach to promote revascularization. However, the availability of a small molecular modulator of this process would provide a break-through for the treatment of diseases and conditions related to insufficient angiogenesis.
The present invention provides a novel method for promoting angiogenesis. The method comprises treating a mammal in need of such therapy with a retinoic acid receptor (RAR) antagonist. The RAR antagonist therapy of the present invention can be used to treat any medical condition associated with suboptimal angiogenesis, such as ischemia and scleroderma. The application of RAR antagonist therapy also finds broad application in the treatment of dermatology, pulmonary and cardiovascular diseases. Applications also include, but are not limited to, promoting angiogenesis for optimal organ function, recanalization of thrombi, development of collateral blood supply for ischemic tissues, including cardiac ischemia, as well as salvage of infarcted myocardium. The use of RAR antagonist therapy to stimulate angiogenesis is also beneficial for the treatment of respiratory aliments such as asthma, emphysema and chronic obstructive pulmonary disease (COPD) where loss of capillary area may promote hypertension and tissue ischemia. The use of RAR antagonist therapy is also beneficial for the treatment of bone fracture.